KMID : 0043320160390060825
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Archives of Pharmacal Research 2016 Volume.39 No. 6 p.825 ~ p.832
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Characterization of the cytotoxic activity of [2]rotaxane (TRO-A0001), a novel supramolecular compound, in cancer cells
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Fujita Yoshihiko
Kimura Masahiko Sato Hiroki Takata Toshikazu Ono Nobufumi Nishio Kazuto
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Abstract
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Rotaxanes comprise a class of interlocked molecules containing a wheel threaded onto an axle with blocking groups on the ends to keep the wheel from sliding off. Here, we show that [2][bis(2-(3,5-dimethylphenylcarbonyloxy)ethyl) ammoniumtrifluoromethanesulfonate]-[dibenzo-24-crown-8] rotaxane (TRO-A0001), a rotaxane compound, exerted a growth inhibitory effect on several human cancer cell lines. An MTT assay revealed an IC50 of 14-830 nM for TRO-A0001 in these cells. Neither the wheel nor the axle part alone inhibited tumor cell growth, suggesting that the complete rotaxane molecule with its unique ¡°intramolecular mobility¡± is required to inhibit cell growth. Annexin-V/PI staining provided evidence of the induction of apoptosis, which was further confirmed by the observation of poly (ADP-ribose) polymerase cleavage. Furthermore, a cell cycle analysis using flow cytometry showed that TRO-A0001 treatment resulted in G1 arrest in glioblastoma T98G and melanoma G361 cells. An immunoblot analysis revealed that in both cell lines, TRO-A0001 treatment caused the induction of p21/Cip1, thereby down-regulating Cdks 2, 4 and 6 and reducing Cyclins D1 and E. The results presented in this study demonstrate cytotoxicity of the rotaxane compound and its potential as a lead compound for the development of a chemotherapeutic agent against cancer.
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KEYWORD
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Rotaxane, Supramolecular compound, Cancer, G1 cell-cycle arrest, p21/Cip1, Apoptosis
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